Bacteria and the bacterial infections that can be treated by antibiotics include, but are not limited to the following:
Staphylococcus aureus, (or “staph”), are bacteria commonly found on the skin and in the noses of healthy people, (F) and are one of the most common causes of skin infections and can also cause serious and sometimes fatal infections (such as bloodstream infections including toxic shock syndrome, impetigo, surgical wound infections, infections of plastic implants, osteomyelitis and pneumonia).
Enterococci, which have been known as a cause of infective endocarditis for close to a century, more recently have been recognized as a cause of nosocomial infection and “superinfection” in patients receiving antimicrobial agents.
Other Gram positive bacteria that can be treated by antibiotics include staphylococcus epidermitis which causes endocarditis, clostridium difficile which causes diarrhea and pseudomembranous colitis, bacillus anthracis of anthrax and streptococcus pneumoniae which causes pneumonia, meningitis, septicemia, and childhood otitis media (or ear-ache). The family of streptococcus bacteria can also be divided into group A or Pyrogenes, which are involved in blood poisoning, glomerularnephritis and fevers such as puerperal, scarlet and rheumatic fever. Group B or streptococcus agalactiae cause neonatal meningitis and pneumonia.
Bacterial Resistance to Antibiotics
Bacterial Infections can occur while in hospital (noscomial), but an additional problem is the increase of infections that are acquired while the person is in the community. A recent study (C) identified the antimicrobial susceptibility profile and resistance mechanisms of pretreatment MRSA isolates obtained from adult subjects participating in recent clinical treatment trials of community respiratory infections. Out of 465 S. aureus isolates, 43 were identified as MRSA. Antimicrobial susceptibility testing indicated susceptibility rates to: vancomycin (100%), gentamicin (86%), clindamycin (39%), quinolones (49%), and erythromycin (12%). All ciprofloxacin-resistant isolates had an amino acid change in GyrA and GrlA. The results indicate that MRSA from adult subjects with community respiratory infections have similar antimicrobial susceptibility profiles and resistance mechanisms as nosocomial MRSA.
The pathogenic potential of Staphylococcus aureus in nosocomial and community-acquired infections is well known. When penicillin was introduced in mid-1940s, S. aureus was almost 94% susceptible to this drug. Widespread resistance to penicillin developed in the 1950s, followed by resistance to semi-synthetic penicillins in the 1960s and 1970s. Since then, strains of methicillin-resistant S. aureus and methicillin-resistant coagulase-neg. staphylococci have spread worldwide. The prevalence of methicillin-resistant S. aureus varies geographically. In Argentina it reaches nearly 50%. Methicillin resistance in staphylococci develops due to the additional. penicillin binding protein PBP2a encoded by gene mecA and is a serious problem both for microbiologists and physicians(A). The high prevalence of methicillin-resistant staphylococci compromises the use of semi-synthetic penicillins for clin. treatments in many institutions, thus increasing the use of vancomycin (a glycopeptide). Until 1996, glycopeptides were almost universally active against S. aureus but it was then that the first glycopeptide-intermediate S. aureus (GISA) also known as VISA (vancomycin intermediately resistant S. aureus) was described and isolated in Japan, followed by France and USA. Infections with Staphylococcus aureus with reduced susceptibility to vancomycin continue to be reported, including 2 cases caused by S. aureus isolates with full resistance to vancomycin. (A) There is also vancomycin-resistant S. aureus (VRSA) The worldwide increase in the incidence of S. aureus clinical isolates with reduced susceptibility to vancomycin and teicoplanin means that glycopeptide resistance in S. aureus is becoming an important clinical problem.
The exact mechanisms involved have not been elucidated yet, although VISA is associated with increased wall synthesis. Many VISA strains are characterized by increased cell wall biosynthesis and decreased crosslinking of the peptide side chains, leading to accumulation of free D-alanyl-D-alanine termini in the peptidoglycan, which it has been proposed can act as false target sites for vancomycin. (B)
The mechanism of vancomycin resistance in enterococcus is well defined and appears to be different to that of VISA.
Vancomycin resistance in enterococci, known as VRE or glycopeptide-resistant enterococci (GRE), exists as either intrinsic resistance where isolates of Enterococcus gallinarum and E. casseliflavus/E. flavescens demonstrate an inherent, low-level resistance to vancomycin or by acquired resistance where Enterococci become resistant to vancomycin by acquisition of genetic information from another organism. Most commonly, this resistance is seen in E. faecium and E. faecalis, but also has been recognized in E. raffinosus, E. avium, E. durans, and several other enterococcal species.
Several genes, including vanA, vanB, vanC, vanD, and vanE, contribute to resistance to vancomycin in enterococci.
E. faecium is the most frequently isolated species of VRE in hospitals and typically produces high vancomycin (>128 μg/ml) and teicoplanin (>16 μg/ml) minimum inhibitory concentrations (MICs). These isolates typically contain vanA genes. The epidemiology of vancomycin-resistant Enterococcus faecium (VREF) in Europe is characterized by a large community reservoir. In contrast, nosocomial outbreaks and infections (without a community reservoir) characterize VREF in the United States. (G)
In vancomycin-susceptible enterococci, D-alanyl-D-alanine (formed by an endogenous D-alanine-D-alanine ligase) is added to a tripeptide precursor to form a pentapeptide precursor. The D-Ala-D-Ala terminus is the target of vancomycin; once vancomycin has bound, the use of this pentapeptide precursor for further cell-wall synthesis is prevented. In the VanA phenotype, one of the proteins whose synthesis is induced by exposure of bacterial cells to vancomycin is called VanA; VanA is a ligase and resembles the D-alanine-D-alanine ligase from Escherichia coli and other organisms, including vancomycin-susceptible enterococci. VanA generates D-Ala-D-X, where X is usually lactate; the formation of D-lactate is due to the presence of VanH, a dehydrogenase encoded by vanH. The depsipeptide moiety, D-Ala-D-Lac, is then added to a tripeptide precursor, resulting in a depsipentapeptide precursor. Vancomycin does not bind to the D-Ala-D-Lac terminus, so this depsipentapeptide can be used in the remaining steps of cell-wall synthesis. However, when the normal pentapeptide precursor ending in D-Ala-D-Ala is also present, cells are not fully vancomycin resistant, despite the presence of D-Ala-D-Lac containing precursors. This apparent problem is taken care of in large part by vanX, which encodes a dipeptidase, VanX, that cleaves D-Ala-D-Ala, preventing its addition to the tripeptide precursor. Should any D-Ala-D-Ala escape cleavage and result in a normal pentapeptide precursor, vanY encodes an ancillary or back-up function. That is, it codes for a carboxypeptidase, VanY, which cleaves D-alanine and D-lactate from D-Ala-D-Ala and D-Ala-D-Lac termini, respectively, resulting in tetrapeptide precursors, to which vancomycin does not bind. The other genes involved in the VanA resistance complex include vanR and vanS, whose encoded proteins are involved in sensing the presence of extracellular vancomycin or its effect and signaling intracellularly to activate transcription of vanH, vanA, and vanX. A final gene in the vanA cluster is vanZ, which encodes VanZ, the role of which is not known. (J)
VanB, encoded by vanB in the vanB gene cluster, is also a ligase that stimulates the formation of D-Ala-D-Lac. The VanB phenotype is typically associated with moderate to high levels of vancomycin resistance but is without resistance to teicoplanin. This is explained by the observation that vancomycin, but not teicoplanin, can induce the synthesis of VanB and of VanHB and VanXB. However, because mutants resistant to teicoplanin can readily be selected from VanB strains on teicoplanin-containing agar, clinical resistance would likely occur among VanB strains if teicoplanin were widely used. Most of the proteins encoded by the vanA gene cluster have homologues encoded by the vanB gene cluster, except for VanZ. The vanB gene cluster has an additional gene, vanW, of unknown function.
The acquired gene clusters associated with vanA and vanB are found in different genetic surroundings. These elements have in turn been found on both transferable and nontransferable plasmids, as well as on the chromosome of the host strain. VanB type resistance was initially not found to be transferable, but at least in some instances, the vanB gene cluster has been found on large (90 kb to 250 kb) chromosomally located transferable elements, More recently, vanB has been found as part of plasmids. (I)
In addition to being found in different genetic surroundings, the vanA and vanB gene clusters have also been found in a number of different bacterial species. vanA has been found in multiple enterococcal species as well as in lactococci, Orskovia, and Arcanobacteria (H). The distribution of the vanB gene cluster seems somewhat more restricted, having been found primarily in E. faecium and E. faecalis, although it has recently been found in Streptococcus bovis (H).
The VanC phenotype (low-level resistance to vancomycin, susceptible to teicoplanin) is an inherent (naturally occurring) property of E. gallinarum and E. casseliflavus. This property is not transferable and is related to the presence of species-specific genes vanC-1 and vanC-2, respectively; a third possible species, E. flavescens and its gene vanC-3, are so closely related to E. casseliflavus and vanC-2 that different names are probably not warranted. These species appear to have two ligases; the cell-wall pentapeptide, at least in E. gallinarum, ends in a mix of D-Ala-D-Ala and D-Ala-D-Ser. The genes vanC-1 and vanC-2 apparently lead to the formation of D-Ala-D-Ser containing cell-wall precursors, while D-Ala-D-Ala ligases, also present in these organisms, result in D-Ala-D-Ala. The presence of both D-Ala-D-Ala and D-Ala-D-Ser precursors may explain why many isolates of these species test susceptible to vancomycin and why even those isolates with decreased susceptibility display only low-level resistance. (J)
VanD-type glycopeptide resistance has been recently described in an E. faecium isolate from the United States (I). The organism was constitutively resistant to vancomycin (MIC>64 μg/ml) and to low levels (4 μg/ml) of teicoplanin. Following polymerase chain reaction amplification with primers that amplify many D-Ala-D-Ala ligases, a 605-bp fragment was identified whose deduced amino acid sequence showed 69% identity to VanA and VanB and 43% identify to VanC.
Bacterial Resistance to Different Classes of Antibiotics.
As well as resistance to approved beta-lactam, glycopeptide antibiotics (including vancomycin, trade name vancocin), and the macrolide-lincosamide-streptogramins (including quinupristin-dalfopristin, trade name synercid) (D) various recent findings have also underlined the importance of biocide resistance as a clin. relevant phenomenon. (D) Outbreaks of biocide-resistant organisms in hospitals have been described and the genetic mechanism for resistance to quaternary ammonium compds. (QACs) in Staphylococcus aureus has now been elucidated.
Some strains of MRSA which have intermediate resistance to glycopeptides were demonstrated to have decreased susceptibility to some biocides including triclosan for which minimal bactericidal concns. (MBCs) increased from 0.002 to 3.12 mg 1-1. Biocide resistance amongst enterococci has also been demonstrated although there was no clear correlation between biocide and antibiotic resistance. The exact mechanisms of resistance in these strains are still being studied but it is clear that biocide resistance is an important clin. phenomenon.
Vancomycin is a cyclic compound. Disclosed herein by reference, WO 03/002545 teaches that ‘peptoid compounds’ made from a peptide chain covalently linked in a cyclic form through a heterocyclic or aromatic ring system have antibacterial activity. The reaction know to those skilled in the art variously as ‘ring closing metathesis’, ‘Grubbs metathesis’ or ‘olefin metathesis’ is taught in WO 03/00254 to join the ends of the molecule which therefore need to terminate in allyl groups (—CH2—CH═CH2) that react in that chemical processes described. The literature (J. Bremner et al New J. Chem, 2002, 26, 1549-1551) teaches that cyclic compounds so made based on a 1,1-binaphthyl scaffold linked in a ring through the 3,3′-positions can have antibacterial activity. Further this literature describes cyclic molecules made from 1,1′-binaphthyl linked through the 2,2′ positions.
Additionally the prior art (J. Bremner et al Tetrahedron, 2003, 59, 8741-8755) teaches that related cyclic compounds (therein known as ‘carbazole linked cyclic peptoids’) can have antibacterial activity.
There is a need for new compounds which are useful in the treatment of bacterial infections, especially those caused by vancomycin resistant organisms.
(A) Staphylococcus aureus with reduced susceptibility to vancomycin. Cosgrove, S. E.; Carroll, K. C.; Perl, T. M. Clinical Infectious Diseases (2004), 39(4), 539-545.
(B) Morphological and genetic differences in two isogenic Staphylococcus aureus strains with decreased susceptibilities to vancomycin. Reipert, A; Ehlert, Kn; Kast, T; Bierbaum, G. Antimicrobial Agents and Chemotherapy (2003), 47(2), 568-576.
(C) Antimicrobial susceptibility and molecular characterization of community-acquired methicillin-resistant Staphylococcus aureus. Almer, L. S.; Shortridge, V. D.; Nilius, A. M.; Beyer, Jill M.; Soni, Niru B.; Bui, Mai H.; Stone, G. G.; Flamm, R. K Diagnostic Microbiology and Infectious Disease (2002), 43(3), 225-232.
(D) Methicillin-resistant, quinupristin-dalfopristin-resistant Staphylococcus aureus with reduced sensitivity to glycopeptides. Werner, G.; Cuny, C.; Schmitz, F.-J.; Witte, W. Journal of Clinical Microbiology (2001), 39(10), 3586-3590.
(E) Susceptibility of antibiotic-resistant cocci to biocides. Fraise, A. P. Society for Applied Microbiology Symposium Series (2002), 31(Antibiotic and Biocide Resistance in Bacteria).
(F) WWW.CDC.gov VISA/VRSA Vancomycin-Intermediate/Resistant Staphylococcus aureus 
(G) Epidemic and nonepidemic multidrug-resistant Enterococcus faecium. Leavis H L, Willems R J L, Top J, Spalburg E, Mascini E M, Fluit A C, et al. Emerg Infect Dis. 2003 September Available from: URL: http://www.cdc.gov/ncidod/EID/vol9no9/02-0383.htm (H) Power E G M, Abdulla Y H, Talsania H G, Spice W, Aathithan S, French G L. vanA genes in vancomycin-resistant clinical isolates of Oerskovia turbata and Arcanobacterium (Corynebacterium) haemolyticum. J Antimicrob Chemother 1995; 36:595-606.
(I) Perichon B, Reynolds P, Courvalin P. VanD-type glycopeptide-resistant Enterococcus faecium BM4339. Antimicrob Agents Chemother 1997; 41:2016-8.
(J) Diversity among Multidrug-Resistant Enterococci Barbara E. Murray, M.D. Emerg Infect Dis. 2003 September. Available from: URL: http://www.cdc.gov/ncidod/EID/vol4no1/murray.htm